1. Technical Field
This invention pertains to a group of novel compounds which exhibit anticonvulsant and neuroprotective properties, methods for their use in controlling seizures or convulsions, and methods of preparing these compounds. The novel compounds of the invention are (+)-3-substituted-N-alkylmorphinans which have been found to have anticonvulsant and neuroprotective properties, their acid addition salts, and pharmaceutical applications for the prevention, treatment and control of seizures and convulsions.
2. Description of Related Art
Morphinans are the parent substance of morphine alkaloids such as codeine and thebaine. Morphine alkaloids and their derivatives have many uses as narcotic analgesics. The basic morphinan structure is similar to the basic morphine structure, but comprehends two configurational isomeric forms, shown in formulas I and II below: ##STR1##
In these formulas, broken lines represent covalent bonds which project below the plane of the reference atoms, while solid wedges or heavily accented lines signify covalent bonds which project above the plane. With this in mind, Formula I, is the L (levorotatory) or (-) enantiomeric form of the basic morphinan structure. Derivatives of this form occur in nature. The enantiomeric morphinan basic structure shown in formula II is the D (dextrorotatory) or (+) isomer, and its derivatives are rarely available in nature, even in trace quantities, and thus can be obtained only, if at all, by means of synthetic preparations.
Derivatives of the antipedal morphinan structures differ markedly in pharmaceutical utility and in the respective mechanisms of their biological activities. The analgesic properties of morphine and of its related naturally occurring (-)-morphinan compounds for treating moderate to severe pain are known. It is presently understood that the biological activity of these compounds results from their binding to the opiate receptor in the central nervous system. Some examples of pharmaceutical uses of compounds belonging to the (-)-morphinan series, the natural opioids, include analgesics (U.S. Pat. No. 3,981,874), and combined analgesic and narcotic antagonist for treating drug dependency (U.S. Pat. Nos. 4,272,540; 4,362,733; and 4,489,079). While the natural opioids have profoundly effective analgesic properties and remain in widespread use, there are serious liabilities associated with their use since natural opioids are narcotic. Use of the natural opioids may induce dependency and other detrimental side effects. Furthermore, tolerance may lead to requirements for increasingly large dosages just to maintain desired analgesic levels.
On the other hand, it has been reported that the unnatural (+)-morphinans bind to distinct receptors in the central nervous system which are different from opiate binding sites. Dextromethorphan, (+)-3-methoxy-N-methylmorphinan, for example, has been found to be a potent antitussive agent (U.S. Pat. No. 4,552,962). More recently, it has been reported by Jose Musacchio and Frank Tortella in U.S. Pat. No. 4,898,860 and Michael Pontecorvo and John Ferkany in U.S. Pat. No. 4,906,638 that dextromethorphan has a potentiating effect on certain antiepileptic or antiseizure compounds such as diphenylhydantoin, phenobarbital, diazepam ketamine, and carbamazepine. The pharmacological use of dextromethorphan has at least one major disadvantage, however, in that it metabolizes rapidly by demethylation in vivo, to dextrorphan, (+)-3-hydroxy-N-methylmorphinan. Dextrorphan is the major dextromethorphan metabolite in man, and has been documented to cause harmful behavioral side effects in addition to having some anticonvulsant activity. Dextromethorphan is not very potent as an anticonvulsant agent and the higher dosages that might be required for desired convulsion control would in turn cause in vivo biosynthesis of dextrorphan by dextromethorphan metabolism, with the attendant detrimental symptoms. At elevated doses, dextromethorphan actually becomes proconvulsant.
Other anticonvulsant agents and combinations are known, but toxicity and other dosage-dependent symptoms remain as challenges to the pharmacological control of epileptic seizures and other kinds of convulsions. Another manifestation of this symptomatology is the interference by some anticonvulsants with the availability in vivo of hydroxycholecalciferol and dihydroxycholecalciferol, metabolic prohormonal forms of vitamin D, evidently caused by the degradation of vitamin D and its metabolites prior to absorption. Other side effects of anticonvulsant treatments include hepatotoxicity and teratogenicity. Furthermore, dextromethorphan and other known anticonvulsion or antiseizure agents are typically effective against only a narrow range of seizure types, leaving some seizure types void of effective control treatment altogether.
It is impossible to predict on the basis of molecular structure alone whether a particular morphinan will have any pharmacological utility. It is apparent that even minute modifications in the composition of the molecule can result in significant changes in pharmacological activity between two structurally similar species. Thus a morphinan belonging to the unnatural series of opioids which possesses the appropriate profile of anticonvulsant and/or neuroprotective actions has potential for treatment or control of convulsions or seizures, or neuroprotection, without the liabilities of drug dependence, drug abuse, or toxic symptoms.
Accordingly, there is a need in the field for the development of anticonvulsant agents that have minimal toxicity and produce few, if any, harmful side effects while being effective against a wide range of seizure types. More specifically, there is a need for anticonvulsant and neuroprotective agents that are effective at dosages that minimize or eliminate drug dependency, poisoning, and other harmful or undesirable side effects.
The present invention provides novel compounds with surprising anticonvulsant, antiseizure and neuroprotective properties, processes for synthesizing novel compounds, and pharmacological methods for using them, without dependence, behavioral modification, toxicity, undesirable side effects, or other liabilities that characterize prior art compounds and treatment methods.